First interim analysis of a phase 1 study of zanubrutinib (zanu) plus lenalidomide (len) in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
Authors: Huilai Zhang, Ying Cheng, Haiyan Yang, Liling Zhang, Liqun Zou, Ye Guo, Junning Cao, Huiqiang Huang, Zhao Wang, Sha Huang, Zhiyu Liang, Jiaoyan Lyu, Yiqian Fang, Aileen Cohen, Keshu Zhou
Journal: Journal of Clinical Oncology (2023)

7557 Background: Effective therapies for R/R DLBCL are limited in China, especially for pts ineligible for high-dose therapy/stem cell transplantation (HDT/SCT). Preclinical data suggest synergy of len with zanu, a potent and selective Bruton tyrosine kinase inhibitor approved for various B-cell malignancies. Here, we present interim analysis results of an ongoing phase 1, open-label, dose-escalation/expansion study of zanu + len in R/R DLBCL (NCT04436107). Methods: Pts with R/R DLBCL ineligible for HDT/SCT with ≥1 prior line of adequate systemic therapy were enrolled. Dose escalation (part 1): Len 15 mg, 20 mg, or 25 mg orally once daily on days 1-21 of each 28-day cycle. Dose expansion (part 2): Len 25 mg. Zanu 160 mg was given orally twice daily continuously in parts 1 and 2. Primary endpoints were safety and recommended phase 2 dose (RP2D) of len (part 1) and overall response rate (ORR) by investigator based on Lugano classification (part 2). Interim analysis was performed when the 19 th pt in part 2 completed first tumor assessment. Pts who received len 25 mg (RP2D) in parts 1 and 2 were analyzed separately. Results: As of November 8, 2022, 46 pts were treated and included in interim analysis (27 in part 1; 19 in part 2; 30 at RP2D). Median age was 60 years (range, 29–82), 83% had stage III–IV disease, 37% had refractory disease, 70% had non-germinal center B-cell (non-GCB) like disease; median number of prior systemic therapies was 1 (range, 1–5). Median exposure to zanu and len was 3.9 months (mo) (range 0.4–24.9), median follow-up was 6.6 mo (range 0.5–25.5). ORR was 46% overall (95% CI: 30.9–61.0; complete response [CR]: 24%) and 57% at RP2D (95% CI: 37.4–74.5; CR: 30%). At RP2D, ORR was 61% (95% CI: 38.5–80.3; CR: 35%) for pts with non-GCB disease and 50.0% (95% CI: 11.8–88.2; CR: 17%) for GCB. At RP2D, median duration of response was not reached and 6-mo event-free rate was 59% (95% CI: 23.8–82.8). Median progression-free survival was 5.5 mo (95% CI: 2.8-not estimable) with a 9-mo event-free rate of 37% (95% CI: 17.6–57.4). Overall, 46 (100%) pts experienced ≥1 treatment-emergent adverse event (TEAE). At RP2D, grade ≥3 TEAEs occurred in 60% of pts, most commonly neutrophil count decreased (43%), white blood cell count decreased (23%), and pneumonia (13%). One pt (2%) had febrile neutropenia (grade 3) but recovered within 2 days. TEAEs led to discontinuation of both len and zanu in 2 pts (cardiopulmonary failure unrelated to treatment [part 1, len 20 mg], pulmonary embolism [part 1, len 25 mg]) and discontinuation of len in 2 pts (platelet count decreased [part 1, len 20 mg], rash [part 2]). Two TEAEs leading to death were reported, unrelated to treatment. Conclusions: Zanu 160 mg plus len 25 mg combination showed an acceptable safety profile with promising efficacy. Further evaluation of the combination in a larger sample size is planned in future analysis. Clinical trial information: NCT04436107 .